Published on Web 05/03/2008
Bidentates versus Monodentates in Asymmetric Hydrogenation Catalysis: Synergic Effects on Rate and Allosteric Effects on Enantioselectivity David W. Norman,† Charles A. Carraz,† David J. Hyett,†,§ Paul G. Pringle,*,† Joseph B. Sweeney,‡ A. Guy Orpen,† Hirrahataya Phetmung,† and Richard L. Wingad† School of Chemistry, UniVersity of Bristol, Cantocks Close, Bristol BS8 1TS, U.K., and Department of Chemistry, UniVersity of Reading, Reading RG6 6AD, U.K. Received February 3, 2008; E-mail:
[email protected] Abstract: C1-Symmetric phosphino/phosphonite ligands are prepared by the reactions of Ph2P(CH2)2P(NMe2)2 with (S)-1,1′-bi-2-naphthol (to give LA) or (S)-10,10′-bi-9-phenanthrol (to give LB). Racemic 10,10′-bi-9-phenanthrol is synthesized in three steps from phenanthrene in 44% overall yield. The complexes [PdCl2(LA,B)] (1a,b), [PtCl2(LA,B)] (2a,b), [Rh(cod)(LA,B)]BF4 (3a,b) and [Rh(LA,B)2]BF4 (4a,b) are reported and the crystal structure of 1a has been determined. A 31P NMR study shows that M, a 1:1 mixture of the monodentates, PMePh2 and methyl monophosphonite L1a (based on (S)-1,1′-bi-2-naphthol), reacts with 1 equiv of [Rh(cod)2]BF4 to give the heteroligand complex [Rh(cod)(PMePh2)(L1a)]BF4 (5) and homoligand complexes [Rh(cod)(PMePh2)2]BF4 (6) and [Rh(cod)(L1a)2]BF4 (7) in the ratio 2:1:1. The same mixture of 5-7 is obtained upon mixing the isolated homoligand complexes 6 and 7 although the equilibrium is only established rapidly in the presence of an excess of PMePh2. The predominant species 5 is a monodentate ligand complex analogue of the chelate 3a. When the mixture of 5–7 is exposed to 5 atm H2 for 1 h (the conditions used for catalyst preactivation in the asymmetric hydrogenation studies), the products are identified as the solvento species [Rh(PMePh2)(L1a)(S)2]BF4 (5′), [Rh(S)2(PMePh2)2]BF4 (6′) and [Rh(S)2(L1a)2]BF4 (7′) and are formed in the same 2:1:1 ratio. The reaction of M with 0.5 equiv of [Rh(cod)2]BF4 gives exclusively the heteroligand complex cis-[Rh(PMePh2)2(L1a)2]BF4 (8), an analogue of 4a. The asymmetric hydrogenation of dehydroamino acid derivatives catalyzed by 3a,b is reported, and the enantioselectivities are compared with those obtained with (a) chelate catalysts derived from analogous diphosphonite ligands L2a and L2b, (b) catalysts based on methyl monophosphonites L1a and L1b, and (c) catalysts derived from mixture M. For the cinnamate and acrylate substrates studied, the catalysts derived from the phosphino/phosphonite bidentates LA,B generally give superior enantioselectivities to the analogous diphosphonites L2a and L2b; these results are rationalized in terms of δ/λ-chelate conformations and allosteric effects of the substrates. The rate of hydrogenation of acrylate substrate A with heterochelate 3a is significantly faster than with the homochelate analogues [Rh(L2a)(cod)]BF4 and [Rh(dppe)(cod)]BF4. A synergic effect on the rate is also observed with the monodentate analogues: the rate of hydrogenation with the mixture containing predominantly heteroligand complex 5 is faster than with the monophosphine complex 6 or monophosphonite complex 7. Thus the hydrogenation catalysis carried out with M and [Rh(cod)2]BF4 is controlled by the dominant and most efficient heteroligand complex 5. In this study, the heterodiphos chelate 3a is shown to be more efficient and gives the opposite sense of optical induction to the heteromonophos analogue 5.
Introduction
shown in eq 1. Moreover, we suggested1 an explanation for
In 2000, it was shown1,2 that optically active monophosphonites based on 1,1′-bi-2-naphthol (binol), such as L1a, gave superior enantioselectivities to their bidentate analogues L2a (Chart 1) in the rhodium-catalyzed asymmetric hydrogenations †
University of Bristol. University of Reading. Current address: DSM Research, P.O. Box 18, 6160 MD Geleen, The Netherlands. (1) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. (2) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333. ‡ §
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this phenomenon in terms of (i) restricted M-P rotations; (ii) the different orientation of the P-C bond in the monodentate and bidentate phosphonites; (iii) the cis preference of phosphonite ligands. These results overturned 25 years of dogma that bidentate phosphorus ligands consistently outperform their monodentate analogues.3 10.1021/ja800858x CCC: $40.75 2008 American Chemical Society
Asymmetric Hydrogenation Catalysis Chart 1. S-Binol Derivatives only Shown
In the same year, Reetz et al.4 reported that monophosphites (LZ, Z ) OR) and de Vries, Feringa et al.5 that monophosphoramidites (LZ, Z ) NR2) gave highly enantioselective hydrogenation catalysts (Chart 1). Both of these groups6 and others7 have subsequently shown that the design of chiral monophos ligands LZ is amenable to high throughput screening techniques. (The term “monophos” is used throughout to mean a monodentate P-donor rather than the DSM trademarked “MonoPhos” family of phosphoramidite ligands.) One striking discovery has been that catalysts based on mixtures of monophos ligands LZ and achiral PY3 (Y ) alkyl, aryl, or OR) can be more active and enantioselective than catalysts derived from monophos ligands LZ alone.8 This implies that, in some cases, the catalyst containing a Rh(LZ)(PY3) moiety is more active and selective than one containing a Rh(LZ)2 moiety. This approach has led to the development by the DSM group of a commercialized asymmetric hydrogenation process.9 The results of the catalysis with the mixed monodentate ligand systems are complicated to interpret because they depend on the proportions of the homoligand {Rh(LZ)2 and Rh(PY3)2} and heteroligand {Rh(LZ)(PY3)} catalysts present (and, in principle, the proportions of rhodium complexes with 0–4 P-donors coordinated10), the rates at which each of these catalyze the hydrogenation, and their enantioselectivity.11,12 Not surprisingly therefore, the enantioselectivity is a sensitive function of LZ, the added PY3, and the prochiral substrate. One advantage that bidentates have over monodentates is control over complex stoichiometry and stereochemistry: in general, a single, cischelate complex of stoichiometry M(diphos) is expected upon the addition of a diphos ligand to a metal catalyst precursor. Indeed several bidentate phosphine/phosphites13,14 and phosphine/phosphoramidites14,15 and a few phosphine/phosphonites16 (3) (a) Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315. (b) Chaloner, P. A.; Esteruelas, M. A.; Joó, F.; Oro, L. A. Homogeneous Hydrogenation; Kluwer: London, 1994. (c) The Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J.,Eds.; WileyVCH: Weinheim, 2007. (4) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. (5) van den Berg, M.; Minnaard, A. J.; Schudd, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. J. Am. Chem. Soc. 2000, 122, 11539. (6) (a) de Vries, J. G.; Lefort, L. Chem. Eur. J. 2006, 12, 4722. and refs therein. (b) Reetz, M. T.; Mehler, G.; Meiswinkel, A. Tetrahedron Asymmetry 2004, 15, 2165. and refs therein. (7) Jäkel, C.; Paciello, R. Chem. ReV. 2006, 106, 2912. (8) (a) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Ninnaard, A. J.; Meetsma, A.; Tiermersma-Wegman, T. D.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 4208. (b) Reetz, M. T.; Bondarev, O. Angew. Chem., Int. Ed. 2007, 46, 4523. (9) de Vries, A. H. M.; Lefort, L.; Boogers, J. A. F.; de Vries, J. G.; Ager, D. J. Chim. Oggi 2005, 23, 18. (10) An IrP1 complex has been shown to be the significant species in Irmonophos-catalyzed asymmetric hydrogenations. Giacomina, F.; Meetsma, A.; Panella, L.; Lefort, L.; de Vries, A. H. M.; de Vries, J. G. Angew. Chem., Int. Ed. 2007, 46, 1497. (11) Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593. (12) Reetz, M. T.; Fu, Y.; Meiswinkel, A. Angew. Chem., Int. Ed. 2006, 45, 1412. (13) Nozaki, K. Chem. Record 2005, 5, 376. and refs therein. (14) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278 and refs therein
ARTICLES Chart 2
have been shown to form excellent chelate catalysts. However, a comparison of the performance of directly analogous heteromonophos and heterodiphos systems has not been reported. In this contribution, the factors that determine the asymmetric hydrogenation catalytic performance of rhodium complexes of mixed phosphine/phosphonite bidentate and monodentate ligands are probed by comparing the results obtained with catalysts derived from the ligands shown in Chart 2. The efficacy of the catalysts derived from the new, bidentate, phosphine/phosphonite ligands LA and LB is compared with the corresponding results for the catalysts derived from (i) the bis(phosphonites) L2a, L2b, L3, and L4,1,17 (ii) the monophosphonites L1a and L1b, and (iii) the mixture (M) of monophosphine PMePh2 and monophosphonite L1a. Results and Discussion Ligand Synthesis. The phosphine/phosphonite ligands LA and LB were readily prepared by the route shown in eq 2 which is an adaptation of King’s method18 for making Ph2PCH2CH2P(OMe)2.
The amidophosphine precursor and optically active binol are commercially available. Racemic 10,10′-bi-9-phenanthrol (biphol) was synthesized as shown in Scheme 1 and resolved by Toda’s method19,20 (see Experimental Section). (15) Wassenaar, J.; Reek, J. N. H. Dalton Trans. 2007, 3750 and refs therein. (16) (a) Schull, T. L.; Knight, D. A. Tetrahedron Asymmetry 1999, 10, 207. (b) Reetz, M. T.; Gosberg, A. Tetrahedron Asymmetry 1999, 10, 2129. (c) Laly, M.; Broussier, R.; Gautheron, B. Tetrahedron Lett. 2000, 41, 1183. (17) (a) Dahlenburg, L. Coord. Chem. ReV. 2005, 249, 2962. and refs therein. (b) Dahlenburg, L. Eur. J. Inorg. Chem. 2003, 2733. and refs therein. (18) King, R. B.; Masler, W. F. J. Am. Chem. Soc. 1977, 99, 4001. (19) Toda, F.; Tanaka, K. J. Org. Chem. 1988, 53, 3607. J. AM. CHEM. SOC.
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Scheme 1
Scheme 3
Scheme 2 Scheme 4
Ligands LA and LB are moderately air-sensitive solids but are indefinitely stable in an inert atmosphere. The 31P NMR spectra of LA and LB were particularly informative of purity: in each case, two doublets were observed with 3J(PP) ≈ 30 Hz. The individual δ(P) values for LA (-11.8, +211.1) are similar to the symmetrical analogues, dppe (-12.5) and L2a (+211.5).1 Coordination Chemistry. The palladium(II) and platinum(II) complexes 1a,b and 2a,b were made according to the routes shown in Scheme 2 (see Experimental Section for the characterizing data). Crystals of 1a suitable for X-ray diffraction were grown by layering pentane on an acetonitrile solution of the complex and the crystal structure of 1a as its acetonitrile solvate has been determined (Figure 1). The crystal system was triclinic, with two molecules of acetonitrile in the unit cell. In the crystal structure of 1a, the five-membered chelate ring has a λ conformation. The Pd-P(binol) bond is significantly shorter than the Pd-PPh2 bond.21 The phosphonite donor apparently has a slightly higher trans influence than the phosphine donor in 1a, since the Pd-Cl bond trans to the P(binol) donor is longer than the Pd-Cl trans to the PPh2 donor albeit by less than 0.02 Å.22 The rhodium coordination chemistry of the heterodiphos ligands, LA and LB, and the mixture of monophos ligands M was investigated because of its relevance to the asymmetric catalysis described below and is summarized in Schemes 3–5. The rhodium complexes 3a,b were made by the reaction of 1 equiv of the corresponding LA or LB with [Rh(cod)2]BF4 (Scheme 3). The 31P NMR data for the phosphine (δ 59.0, J(RhP) 154 Hz) and phosphonite (δ 206.8, J(RhP) 222 Hz) moieties in 3a are similar to the data for the homochelates (20) An alternative procedure for the synthesis of optically active biphol has recently been reported. Ayudin, J.; Kumar, K. S.; Sayah, M. J.; Wallner, O. A.; Szabó, K. J. J. Org. Chem. 2007, 72, 4689. (21) Atherton, M. J.; Fawcett, J.; Hill, A. P.; Holloway, J. H.; Hope, E. G.; Russell, D. R.; Saunders, G. C.; Stead, R. M. J. J. Chem. Soc., Dalton Trans. 1997, 1137. (22) Martín, A.; Orpen, A. G. J. Am. Chem. Soc. 1996, 118, 1464. 6842
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[Rh(cod)(dppe)]BF4 (δ 56.5, J(RhP) 148 Hz)23 and [Rh(cod)(L2a)]BF4 (δ 205.7, J(RhP) 229 Hz)1 indicating that the P-environments in the heterochelate 3a are similar to their homochelate analogues. When more than 1 equiv of LA or LB was added to [Rh(cod)2]BF4, in each case a new product formed whose 31P NMR spectrum was a symmetrical AA′MM′X pattern. The data (see Experimental Section) are consistent with the formation of the bis-chelates 4a or 4b in which the phosphine donors are mutually cis. The products formed upon treatment of M with 1 equiv of [Rh(cod)2]BF4 were investigated by 31P NMR spectroscopy. The spectrum obtained was consistent with the presence of complexes 5-7 (Scheme 4) in approximately the statistical 2:1:1 ratio. Precisely the same mixture of products was obtained after mixing the homoligand rhodium(I) complexes 624 and 71 in a 1:1 ratio in CH2Cl2. These experiments show that complexes 5-7 are in dynamic equilibrium (Scheme 4). The 31P NMR data for the heteroligand complex 5 are similar to those for 3a except the values of δ(P) are, as expected,25 to low frequency of those for the five-membered chelate 3a. (23) de Wolf, E.; Spek, A. L.; Kuipers, B. W. M.; Philipse, A. P.; Meeldijk, J. D.; Bomans, P. H. H.; Frederik, P. M.; Deelman, B-J.; van Koten, G. Tetrahedron 2002, 58, 3911. (24) Osborn, J. A.; Schrock, R. R. J. Am. Chem. Soc. 1971, 93, 2397. (25) Appleton, T. G.; Bennett, M. A.; Tomkins, I. B. J. Chem. Soc., Dalton Trans. 1976, 439.
Asymmetric Hydrogenation Catalysis
ARTICLES Scheme 5
Figure 1. Solid-state molecular structure of 1a (S-isomer). Hydrogen atoms have been omitted for clarity. Selected bond lengths (Å) and angles (deg): Pd(1)-P(1) ) 2.1933(9), Pd(1)-P(2) ) 2.2525(9), Pd(1)-Cl(1) ) 2.3621(9), Pd(1)-Cl(2) ) 2.3790(9), P(1)-O(1) ) 1.607(2), P(1)-O(2) ) 1.601(2), P(1)-C(2) ) 1.807(4), P(2)-C(1) ) 1.845(3), P(2)-C(21) ) 1.818(4),P(2)-C(31))1.822(3);P(1)-Pd(1)-P(2))85.40(3),P(1)-Pd(1)-Cl(1) ) 90.50(3), P(2)-Pd(1)-Cl(2) ) 88.62(3), Cl(1)-Pd(1)-Cl(2) ) 95.61(3).
It was noted that the equilibrium in Scheme 4 took up to 1 h to be established but was reduced to 5 min by the addition of PMePh2 which catalyzes the ligand exchange. Thus, in order to obtain reproducible results in the hydrogenations with M (see below), the isolated complexes 6 and 7 were mixed in the presence of 0.1 equiv of PMePh2. In addition, the catalyst was activated by submitting it to 5 atm of H2 for 1 h to obviate any potential problems in interpreting the results due to 1,5-cyclooctadiene hydrogenation.26 The 31P NMR spectrum of the products of hydrogenation of the mixture of 5–7 showed the presence of three species in the ratio of 2:1:1 (see Scheme 4). The major component was assigned the structure 5′ on the basis of the AMX 31P NMR pattern and the absence of hydride signals in the 1H NMR spectrum of the mixture. The two minor products (doublets in the 31P NMR spectrum) were assigned to the solvento complexes 6′ and 7′ (see Experimental Section for the data). It was apparent that the ratio in the 5–7 mixture was similar to the ratio of the derivatives 5′–7′. When the mixture M was added to 0.5 equiv of [Rh(cod)2]BF4 in CH2Cl2, a single species was formed and assigned the structure 8 (Scheme 5) on the basis of the AA′MM′X pattern in the 31P NMR spectrum which was similar to that observed for the bis-chelate analogue 4a. The same species 8 is also the product of the addition of L1a to 6 or PMePh2 to 7 (Scheme 5). Compound 8 was only detected when the ratio of mixture M to Rh exceeded 1:1. In the catalysis experiments below, an excess of M was avoided since we found that 8 had very low activity and gave essentially racemic hydrogenation products. Asymmetric Hydrogenation Catalysis. The chelates 3a,b were screened for asymmetric hydrogenation of the substrates A-F (Chart 3), and the results are collected in Table 1. In general, the biphol-derived catalyst 3b was more selective for these substrates than the binol-derived catalyst 3a. The variation in the enantioselectivity with the cinnamic acid derivatives B-F (entries 1 and 2, Table 1) shows the sensitivity of the catalysts to subtle changes in the substrate structure. When (26) Cobley, C. J.; Lennon, I. C.; McCague, R.; Ramsden, J. A.; ZanottiGerosa, A. Tetrahedron Lett. 2001, 42, 7481.
Table 1. Asymmetric Hydrogenations of Substrates A-Fa substrate/eeb entry
ligand
catalyst
A
B
C
D
E
F
1 2 3 4
LA LB LA LA
3a 3b in situ 4a
74 94 53 55
69 96 57 51
>99 >99
78 n.d.
72 92
n.d. 96
a Conditions: in CH2Cl2, 5 bar H2, 25 °C, 1 mol % catalyst, 1 h; conversions were 100% (see Experimental Section for full details). b The %R enantiomer formed in excess.
Chart 3
the catalyst used was made in situ by addition of LA to [Rh(cod)2]BF4 rather than preformed 3a, the rates of hydrogenation were slower and the ee was lower (entry 3, Table 1); in fact the results were similar to those obtained with the preformed bis-chelate 4a (entry 4, Table 1). The hydrogenation of substrate B was carried out with preformed 3a and 3b at higher (25 atm) and lower (1 atm) pressure of H2; this had no effect on the enantioselectivities, but the rates of hydrogenation were faster at higher H2 pressure. The efficiency of the heterochelate catalyst 3a for hydrogenation of substrate A was compared with those of the homochelates [Rh(cod)(L2a)]BF4 and [Rh(cod)(dppe)]BF4 by monitoring the substrate conversion as a function of time. Under the same reaction conditions (see Experimental Section), after 3 min, the conversion of substrate A using 3a as catalyst was 95%, using [Rh(cod)(L2a)]BF4 as catalyst was 33%, and using [Rh(cod)(dppe)]BF4 as catalyst was 8%. These experiments show that having a mixed P-donor set in this case leads to a significant enhancement in rate; we27,28 and others13 have previously noted a synergic effect on the rates of catalysis with mixed P-donor catalysts. (27) Carraz, C. A.; Ditzel, E. J.; Orpen, A. G.; Ellis, D. D.; Pringle, P. G.; Sunley, G. J. Chem. Commun. 2000, 1277. (28) Basra, S.; de Vries, J. G.; Hyett, D. J.; Harrison, G.; Heslop, K. M.; Orpen, A. G.; Pringle, P. G.; von der Luehe, K. Dalton Trans. 2004, 1901. J. AM. CHEM. SOC.
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Table 2. Comparison of Asymmetric Hydrogenations of Substrates A and Ba eec b
entry
ligand
A
B
1 2 3 4 5 6 7 8 9
LA LB L2a L2b L3 L4 L1a L1b Md
74 94 90 23 89 26 93 29 -40
69 96 19 14 85 36 92 -14 -27
ref
this this 1 1 17 17 this 1 this
work work
work work
a Conditions in this work: 5 bar H2, 25 °C, CH2Cl2 (unless otherwise stated), 1 mol % catalyst (see Experimental Section for full details). b Preformed rhodium complexes were used unless otherwise stated. c The %R-enantiomer formed in excess; a negative number indicates that the S-enantiomer was in excess. d This catalyst was generated by mixing complexes 6 and 7 (see Experimental Section ) in a 5:1 mixture of EtOAc/CH2Cl2. In pure CH2Cl2, the ee was -14% with substrate A and -11% with substrate B.
The data collected in Table 2 will be used to discuss the results obtained for the asymmetric hydrogenations of substrates A and B with catalysts derived from the ligands shown in Chart 2. The bidentate ligands LA, LB, L2a, and L2b all contain the flexible PCH2CH2P unit which allows the metal chelate rings to adopt chiral δ and λ conformations (Figure 2a). Rapid ring inversion would be expected,29 but these conformers will not be equally populated in solution because they are diastereoisomers, by virtue of the S-binol or S-biphol substitutents. In terms of the catalyst enantioselectivity, one of the diastereoisomers will be the matched isomer, and the other, the mismatched isomer. The ee obtained will depend on the relative abundance of the two diastereoisomers and their catalytic activity and enantioselectivity. Dahlenburg17 has convincingly demonstrated, with evidence from the S-binol-derived ligands L3 and L4 which have enforced δ and λ conformations (Figure 2b), that the δ chelate is the matched isomer, i.e. for the hydrogenation of substrates A and B, the catalyst derived from L3 gave higher R-enantioselectivity than the catalyst derived from L4 (see entries 5 and 6). They argued that upper-left/lower-right quadrant blocking (which favors R-enantioselectivity30) by the S-binol substituents was reinforced by the δ conformation of the chelate which puts the blocking groups in a more effective pseudoaxial site. The crystal structures of [PdCl2(LA)] and [PtCl2(L2b)]1 reproduced in Figure 3 corroborate this explanation: in the δ conformer [PdCl2(LA)] (Figure 3a) the upper-left quadrant is clearly more blocked than in the λ conformer [PtCl2(L2b)] (Figure 3b). We suggest that solutions of the catalysts derived from L2a and L2b contain mixtures of matched (S,S-δ) and mismatched (S,S-λ) chelates (Figure 2a).31 The high ee obtained in the hydrogenation of substrate A with the catalyst derived from L2a is consistent with the catalyst behaving as the matched S,S-δ species (compare entries 3 and 5, Table 2) whereas the low ee obtained for substrate B with the same catalyst is consistent with the catalyst behaving as (29) Fernandez, E.; Gillon, A.; Heslop, K.; Horwood, E.; Hyettt, D. J.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 1663. (30) Gridnev, I.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633. (31) The 31P NMR spectrum of [Rh(cod)(L2a)]BF4 and [Rh(cod)(LA)]BF4 in CH2Cl2 solution showed only one set of signals even at-80°C; this could be because only one conformer is present at NMR-detectable levels or, more likely, that the λ and δ conformers are in rapid equilibrium with a low-energy barrier to ring inversion. 6844
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the mismatched S,S-λ species (entries 3 and 6, Table 2). It appears that the conformation (or shape) of the catalyst responds to the substrate, i.e., an allosteric effect.32 Support for the suggestion that the substrate can influence the chelate conformation comes from the crystal structures of complexes of the type [Rh(diphos)(η4diene)]+ which show that the adoption of a δ or λ chelate conformation depends on the diene.33 There is a striking contrast between the high enantioselectivities obtained with biphol-heterochelate [Rh(cod)(LB)]BF4 (entry 2, Table 2) and the low enantioselectivities obtained with biphol-homochelate [Rh(cod)(L2b)]BF4 (entry 4, Table 2). As above, we suggest that at least part of the explanation for this is the difference in populations and/or activities of the matched and mismatched conformers. Inspection of the enantioselectivities obtained with the catalysts derived from analogous monophosphonite and diphosphonite catalysts reveals complicated behavior. The catalyst derived from the binol-monodentate L1a gave higher ee’s (entry 7, Table 2) than the analogous diphos L2a (entry 3, Table 2), whereas the biphol-derived monodentate L1b and diphos L2b both gave poor ee’s (entries 4 and 8, Table 2). The greater conformational flexibility of monodentate P-complexes (via Rh-P rotation) than analogous diphos complexes coupled with an incomplete understanding of the mechanism of the hydrogenation with monodentate P-catalysts10,34,35 makes interpretation of these enantioselectivities fraught with difficulties. The distinction is clearer when the unsymmetrical diphos LA (entry 1, Table 2) is compared with the mixture of monodentates M (entry 9, Table 2). The catalyst derived from the mixture M not only gives lower ee’s than LA but the sense of optical induction is opposite. Reetz et al. reported a similar inversion of optical induction with catalysts derived from mixtures of chiral phosphites and achiral phosphines.11 Assuming the catalysts 5–7 act independently, the net S-selectivity must be due to the mixed monodentate complex 5 since 6 is achiral and 7 gives R-product (Entry 7, Table 2). To probe this further, the hydrogenation of A catalyzed by 6, 7, and the 2:1:1 mixture of 5–7 derived from M was monitored by measuring the conversions to product as a function of time. Under the same reaction conditions (see Experimental Section), with the same Rh concentrations, after 3 min, the conversions were, 95% using mixture 5–7 as catalyst, 50% using [Rh(cod)(PMePh2)2]BF4 (6) as catalyst, and 60% using [Rh(cod)(L1a)2]BF4 (7) as catalyst. Thus, as with the heterodiphos catalyst 3a, the heteromonophos catalyst 5 shows a synergic effect of the mixed donors on the rate of catalysis. This kinetic advantage offers the prospect of phosphonite/phosphine mixtures being discovered that yield efficient and selective catalysts. Conclusion
Monodentate P-ligands have made a great impact on asymmetric hydrogenation catalysis in recent years. From the discovery of (32) (a) Allosteric effects are normally associated with enzyme catalysts although synthetic catalysts are known that show allosteric effects; see: Merlau, M. L.; Mejia, M. P.; Nguyen, S. T.; Hupp, J. T. Angew. Chem., Int. Ed. 2001, 40, 4239. (b) Gianneschi, N. C.; Bertin, P. A.; Nguyen, S. T.; Mirkin, C. A.; Zakharov, L. N.; Rheingold, A. L. J. Am. Chem. Soc. 2003, 125, 10508. (c) We have previously suggested an allosteric effect with an asymmetric hydrogenation catalyst; see: Baber, A.; de Vries, J. G.; Orpen, A. G.; Pringle, P. G.; von der Luehe, K. Dalton Trans. 2006, 4821. (33) Tsuruta, H.; Imamoto, T.; Yamaguchi, K.; Gridnev, I. D. Tetrahedron Lett. 2005, 46, 2879. (34) Gridnev, I. D.; Fan, C.; Pringle, P. G. Chem. Commun. 2007, 1319.
Asymmetric Hydrogenation Catalysis
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Figure 2. (a) Schematic of the δ/λ conformer equilibrium for a ligand with a flexible C2-backbone; (b) Dahlensburg’s ligands which give δ and λ chelate conformers respectively enforced by the rigid C2-backbone.17
more difficult to predict, with the rotationally less constrained monodentate P-ligands, as implied by the opposite sense of induction observed with the heterodiphos and analogous heteromonophos systems described here. Further mechanistic studies aimed at deepening the understanding of these important features are in progress.34 Experimental Section
Figure 3. Crystal structures of (a) [PdCl2(LA)] (1a) and (b) [PtCl2(L2b)]1
(with phenanthrene fragments truncated for ease of comparison) showing the δ and λ chelate conformations and their effect on the upper-left quadrant blocking.
effective combinations of achiral and optically active monodentates has emerged a powerful high throughput protocol for tailoring catalysts to a particular substrate. The comparison of the heterobidentate phosphino/phosphonite LA and the monophosphonite/ monophosphine analogue M presented in this article has revealed that the greater activity of the heteroligand catalysts compared to that of the homoligand catalysts is true for the bidentate and monodentate systems. The synergic effect of the heteroligands on the rate explains why the heteromonodentates dominate the catalysis in mixed monodentate systems. It is well-known that the performance of many asymmetric hydrogenation catalysts is sensitive to the substrate,36 and here we have argued that chelate catalysts with flexible backbones will be particularly prone to this sensitivity because of substrateinduced conformational changes, i.e. allosteric effects. For example, the observation of the contrasting performances of the five-membered chelates formed by the diphosphonites L2a, L2b and the phosphine/phosphonites LA, LB can be partly explained by differences in populations and activities of matched (δ) and mismatched (λ) conformers of the chelate catalysts. Conformational preferences will certainly be important, but inevitably (35) Reetz, M. T.; Meiswinkel, A.; Mehler, G.; Angermund, K.; Graf, M.; Thiel, T.; Mynott, R.; Blackmond, D. G. J. Am. Chem. Soc. 2005, 127, 10305. (36) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
Unless otherwise stated, all work was carried out under a dry nitrogen atmosphere, using standard Schlenk line techniques. Dry N2-saturated solvents were collected from a Grubbs system37 in flame- and vacuum-dried glassware. Anhydrous methanol and pentane were purchased from Aldrich and were degassed prior to use by bubbling with dry nitrogen. 2,2-Dimethoxypropane was freshly distilled prior to use. [PtCl2(cod)],38 [PdCl2(NCPh)2],39 and [Rh(cod)2]BF4,40 were prepared by literature methods. (S)-(-)-1,1′bi-2-naphthol was purchased from Syncom BV, Groningen and Ph2P(CH2)2P(NMe2)2 was purchased from EPP Ltd. (Edinburgh). Substrates C-F were supplied by DSM chemicals. All other starting materials were purchased from Aldrich. Unless otherwise stated, 1 H, 13C, and 31P NMR spectra were recorded at 300, 75, and 121 MHz respectively at +23 °C on a Jeol ECP 300 spectrometer. Mass spectra were recorded on a Fisons MD800 (FAB), a VG Analytical Quattro (ESI) or a VG Analytical Autospec (EI). Elemental analyses were carried out by the Microanalytical Laboratory of the School of Chemistry, University of Bristol. 9-Hydroxyphenanthrene. This precursor was prepared in pure form for the coupling reaction to racemic 10,10′-bi-9-phenanthrol described below since the commercially available technical grade of 9-hydroxyphenanthrene was found to be unsuitable for the coupling reaction. Magnesium turnings (2.08 g, 86 mmol) were activated overnight by vigorous stirring under nitrogen. A dropping funnel was charged with a solution of 9-bromophenanthrene (20.04 g, 78 mmol) in tetrahydrofuran (65 cm3). Enough of this solution was added to cover the magnesium turnings followed by the rest of the solution dropwise. After the addition, the mixture was refluxed for 20 h followed by cooling to room temperature to give the Grignard reagent. In a separate flask a solution of trimethylborate (9.6 cm3, 86 mmol) in tetrahydrofuran (65 cm3) was cooled to -10 °C, and the Grignard was added dropwise while maintaining the temperature below 0 °C. The solution was stirred for 1 h at -5 °C and then recooled to -10 °C. Glacial acetic acid (7 cm3) was added followed by a solution of 30% aqueous hydrogen peroxide (8.7 cm3) in water (7.9 cm3) while maintaining the solution at
